rs370539038

Variant names:

• chr12-55955270-T-TTACCTATATATATATATA
• rs370539038
• NM_001384361.1:c.1850+3_1850+4insTATATATATATATAGGTA

Your query was ambiguous. Multiple possible variants found:

• chr12-55955270-T-TTACCTATATATATATATA
• chr12-55955270-T-TTACCTATATATATATA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001384361.1(PMEL):​c.1850+3_1850+4insTATATATATATATAGGTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,600,952 control chromosomes in the GnomAD database, including 11 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0058 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (3 hom.)
• Consequence: PMEL NM_001384361.1 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.160
• Publications: 0 publications found

Genes affected

PMEL (HGNC:10880): (premelanosome protein) This gene encodes a melanocyte-specific type I transmembrane glycoprotein. The encoded protein is enriched in melanosomes, which are the melanin-producing organelles in melanocytes, and plays an essential role in the structural organization of premelanosomes. This protein is involved in generating internal matrix fibers that define the transition from Stage I to Stage II melanosomes. This protein undergoes a complex pattern of prosttranslational processing and modification that is essential to the proper functioning of the protein. A secreted form of this protein that is released by proteolytic ectodomain shedding may be used as a melanoma-specific serum marker. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2011]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 12-55955270-T-TTACCTATATATATATATA is Benign according to our data. Variant chr12-55955270-T-TTACCTATATATATATATA is described in ClinVar as Benign. ClinVar VariationId is 781077.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00579 (882/152258) while in subpopulation AFR AF = 0.0205 (853/41522). AF 95% confidence interval is 0.0194. There are 8 homozygotes in GnomAd4. There are 425 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384361.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMEL	NM_001384361.1	MANE Select	c.1850+3_1850+4insTATATATATATATAGGTA		splice_region intron	N/A	NP_001371290.1	P40967-1
	PMEL	NM_001200054.1		c.1871+3_1871+4insTATATATATATATAGGTA		splice_region intron	N/A	NP_001186983.1	P40967-2
	PMEL	NM_006928.5		c.1850+3_1850+4insTATATATATATATAGGTA		splice_region intron	N/A	NP_008859.1	P40967-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMEL	ENST00000548747.6	TSL:1 MANE Select	c.1850+3_1850+4insTATATATATATATAGGTA		splice_region intron	N/A	ENSP00000448828.1	P40967-1
	PMEL	ENST00000449260.6	TSL:1	c.1871+3_1871+4insTATATATATATATAGGTA		splice_region intron	N/A	ENSP00000402758.2	P40967-2
	PMEL	ENST00000548493.5	TSL:2	c.1850+3_1850+4insTATATATATATATAGGTA		splice_region intron	N/A	ENSP00000447374.1	P40967-1

Frequencies

GnomAD3 genomes AF: 0.00580 AC: 882 AN: 152140 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000760 AC: 191 AN: 251200 AF XY: 0.000589

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000544 AC: 788 AN: 1448694 Hom.: 3 Cov.: 28 AF XY: 0.000462 AC XY: 333 AN XY: 721516

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0213 AC: 704 AN: 33018

American (AMR) AF: 0.000582 AC: 26 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 85978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000364 AC: 4 AN: 1100156

Other (OTH) AF: 0.000900 AC: 54 AN: 59990

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00579 AC: 882 AN: 152258 Hom.: 8 Cov.: 32 AF XY: 0.00571 AC XY: 425 AN XY: 74458

African (AFR) AF: 0.0205 AC: 853 AN: 41522

American (AMR) AF: 0.00144 AC: 22 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00296 Hom.: 1

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.16
Mutation Taster		=93/7	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs370539038; hg19: chr12-56349054;